The mechanisms leading to CD4 T cell depletion in HIV-infected individuals remain to be determined. Certain viral infections including HIV infection lead to a chronic activation state of the immune system that results in an enhanced state of susceptibility to apoptosis in a variety of immune cells. In addition, HIV infection specifically triggers an enhanced level of susceptibility to Fas-dependent apoptosis in peripheral CD4 T cells. A second HIV specific sequelae is the induction of FasL expression in antigen presenting cells such as macrophages. Based on the preferential and specific interaction between CD4 T cells and macrophages, this proposal will address the hypothesis that encounter of the Fas susceptible CD4 T cell with a FasL expressing macrophage leads to selective depletion of the CD4 T cells. Preliminary data demonstrate that both mechanisms, increased susceptibility to Fas in CD4 T cells, and increased FasL expression in macrophages, is observed not only in in vitro models but in HIV-infected patients. Understanding the molecular mechanisms regulating susceptibility of primary CD4 T cells to Fas-dependent apoptosis (Aim I), and identifying the regulation of FasL expression in macrophages by HIV-dependent mechanisms (Aim II) will be used to test relevance in HIV-infected patients (Aim III). Results from these three aims should establish the clinical relevance of the HIV induced dysregulation of Fas/FasL interactions as a cause of CD4 T cell depletion in HIV-infected patients.